Browsing by Author "Chuang, Trees-Juen"

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CAPIH: A Web interface for comparative analyses and visualization of host-HIV protein-protein interactions
(2009-08-12)
Lin, Fan-Kai
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Pan, Chia-Lin
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Yang, Jinn-Moon
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Chuang, Trees-Juen
;
Chen, Feng-Chi
Background: The Human Immunodeficiency Virus type one (HIV-1) is the major causing pathogen of the Acquired Immune Deficiency Syndrome (AIDS). A large number of HIV-1-related studies are based on three non-human model animals: chimpanzee, rhesus macaque, and mouse. However, the differences in host-HIV-1 interactions between human and these model organisms have remained unexplored. Description: Here we present CAPIH (Comparative Analysis of Protein Interactions for HIV-1), the first web-based interface to provide comparative information between human and the three model organisms in the context of host-HIV-1 protein interactions. CAPIH identifies genetic changes that occur in HIV-1-interacting host proteins. In a total of 1,370 orthologous protein sets, CAPIH identifies similar to 86,000 amino acid substitutions, similar to 21,000 insertions/deletions, and similar to 33,000 potential post-translational modifications that occur only in one of the four compared species. CAPIH also provides an interactive interface to display the host-HIV-1 protein interaction networks, the presence/absence of orthologous proteins in the model organisms in the networks, the genetic changes that occur in the protein nodes, and the functional domains and potential protein interaction hot sites that may be affected by the genetic changes. The CAPIH interface is freely accessible at http://bioinfo-dbb.nhri.org.tw/capih. Conclusion: CAPIH exemplifies that large divergences exist in disease-associated proteins between human and the model animals. Since all of the newly developed medications must be tested in model animals before entering clinical trials, it is advisable that comparative analyses be performed to ensure proper translations of animal-based studies. In the case of AIDS, the host-IV-1 protein interactions apparently have differed to a great extent among the compared species. An integrated protein network comparison among the four species will probably shed new lights on AIDS studies.
DNA Methylation is Associated with an Increased Level of Conservation at Nondegenerate Nucleotides in Mammals
(2014-02-01)
Chuang, Trees-Juen
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Chen, Feng-Chi
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生物科技學系
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Department of Biological Science and Technology
DNA methylation at CpG dinucleotides can significantly increase the rate of cytosine-to-thymine mutations and the level of sequence divergence. Although the correlations between DNA methylation and genomic sequence evolution have been widely studied, an unaddressed yet fundamental question is how DNA methylation is associated with the conservation of individual nucleotides in different sequence contexts. Here, we demonstrate that in mammalian exons, the correlations between DNA methylation and the conservation of individual nucleotides are dependent on the type of exonic sequence (coding or untranslated), the degeneracy of coding nucleotides, background selection pressure, and the relative position (first or nonfirst exon in the transcript) where the nucleotides are located. For untranslated and nonzero-fold degenerate nucleotides, methylated sites are less conserved than unmethylated sites regardless of background selection pressure and the relative position of the exon. For zero-fold degenerate (or nondegenerate) nucleotides, however, the reverse trend is observed in nonfirst coding exons and first coding exons that are under stringent background selection pressure. Furthermore, cytosine-to-thymine mutations at methylated zero-fold degenerate nucleotides are predicted to be more detrimental than those that occur at unmethylated nucleotides. As zero-fold and nonzero-fold degenerate nucleotides are very close to each other, our results suggest that the "functional resolution" of DNA methylation may be finer than previously recognized. In addition, the positive correlation between CpG methylation and the level of conservation at zero-fold degenerate nucleotides implies that CpG methylation may serve as an "indicator" of functional importance of these nucleotides.
Identification and analysis of ancestral hominoid transcriptome inferred from cross-species transcript and processed pseudogene comparisons
(2008-07-01)
Huang, Yao-Ting
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Chen, Feng-Chi
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Chen, Chiuan-Jung
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Chen, Hsin-Liang
;
Chuang, Trees-Juen
Comparative transcriptomics studies in hominoids are difficult because of lack of EST information in the great apes. Nevertheless, processed pseudogenes (PPGs), which are reverse-transcribed ancient transcripts present in the current genome, can be regarded as a virtual transcript resource that may compensate for the paucity of ESTs in non-human hominoids. Here we show that chimpanzee PPGs can be applied to identification of novel human exons/alternatively spliced variants (ASVs) and inference of the ancestral hominoid transcriptome and chimpanzee exon loss events. We develop a method for comparatively extracting novel transcripts from PPGs ( designated "CENTP") and identify 643 novel human exons/ASVs. RT-PCR-sequencing experiments confirmed > 50% of the tested exons/ASVs, supporting the effectiveness of the CENTP pipeline. With reference to the ancestral transcriptome inferred by CENTP, 47 chimpanzee exon loss events are identified. Furthermore, by combining out-group and PPG information, we identify 20 chimpanzee-specific exon loss and 10 human-specific exon gain events. We also demonstrate that the ancestral transcriptome and exon loss/gain events inferred based on comparisons of current transcripts may be incomplete ( or occasionally inappropriate) because ancestral transcripts may not be represented in the ESTs of existing species. Finally, functional analysis reveals that the novel exons identified based on chimpanzee transcripts are significantly enriched in genes related to translation regulatory activity and viral life cycle, suggesting different expression levels of the associated transcripts, and thus divergent splicing isoform composition between human and chimpanzee in these functional categories.
Position-dependent correlations between DNA methylation and the evolutionary rates of mammalian coding exons
(2012-09-25)
Chuang, Trees-Juen
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Chen, Feng-Chi
;
Chen, Yen-Zho
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生物科技學系
;
Department of Biological Science and Technology
DNA cytosine methylation is a central epigenetic marker that is usually mutagenic and may increase the level of sequence divergence. However, methylated genes have been reported to evolve more slowly than unmethylated genes. Hence, there is a controversy on whether DNA methylation is correlated with increased or decreased protein evolutionary rates. We hypothesize that this controversy has resulted from the differential correlations between DNA methylation and the evolutionary rates of coding exons in different genic positions. To test this hypothesis, we compare human-mouse and human-macaque exonic evolutionary rates against experimentally determined single-base resolution DNA methylation data derived from multiple human cell types. We show that DNA methylation is significantly related to within-gene variations in evolutionary rates. First, DNA methylation level is more strongly correlated with C-to-T mutations at CpG dinucleotides in the first coding exons than in the internal and last exons, although it is positively correlated with the synonymous substitution rate in all exon positions. Second, for the first exons, DNA methylation level is negatively correlated with exonic expression level, but positively correlated with both nonsynonymous substitution rate and the sample specificity of DNA methylation level. For the internal and last exons, however, we observe the opposite correlations. Our results imply that DNA methylation level is differentially correlated with the biological (and evolutionary) features of coding exons in different genic positions. The first exons appear more prone to the mutagenic effects, whereas the other exons are more influenced by the regulatory effects of DNA methylation.
Scanning for the Signatures of Positive Selection for Human-Specific Insertions and Deletions
(2009)
Chen, Chun-Hsi
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Chuang, Trees-Juen
;
Liao, Ben-Yang
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Chen, Feng-Chi
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生物科技學系
Human-specific small insertions and deletions (HS indels, with lengths <100 bp) are reported to be ubiquitous in the human genome. However, whether these indels contribute to human-specific traits remains unclear. Here we employ a modified McDonald-Kreitman (MK) test and a combinatorial population genetics approach to infer, respectively, the occurrence of positive selection and recent selective sweep events associated with HS indels. We first extract 625,890 HS indels from the human-chimpanzee-macaque-mouse multiple alignments and classify them into nonpolymorphic (41%) and polymorphic (59%) indels with reference to the human indel polymorphism data. The modified MK test is then applied to 100-kb partially overlapped sliding windows across the human genome to scan for the signs of positive selection. After excluding the possibility of biased gene conversion and controlling for false discovery rate, we show that HS indels are potentially positively selected in about 10 Mb of the human genome. Furthermore, the indel-associated positively selected regions overlap with genes more often than expected. However, our result suggests that the potential targets of positive selection are located in noncoding regions. Meanwhile, we also demonstrate that the genomic regions surrounding HS indels are more frequently involved in recent selective sweep than the other regions. In addition, HS indels are associated with distinct recent selective sweep events in different human subpopulations. Our results suggest that HS indels may have been associated with human adaptive changes at both the species level and the subpopulation level.
Selective Constraint on Human Pre-mRNA Splicing by Protein Structural Properties
(2012)
Gelly, Jean-Christophe
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Lin, Hsuan-Yu
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de Brevern, Alexandre G.
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Chuang, Trees-Juen
;
Chen, Feng-Chi
Alternative splicing (AS) is a major mechanism of increasing proteome diversity in complex organisms. Different AS transcript isoforms may be translated into peptide sequences of significantly different lengths and amino acid compositions. One important question, then, is how AS is constrained by protein structural requirements while peptide sequences may be significantly changed in AS events. Here, we address this issue by examining whether the intactness of three-dimensional protein structural units (compact units in protein structures, namely protein units [PUs]) tends to be preserved in AS events in human. We show that PUs tend to occur in constitutively spliced exons and to overlap constitutive exon boundaries. Furthermore, when PUs are located at the boundaries between two alternatively spliced exons (ASEs), these neighboring ASEs tend to co-occur in different transcript isoforms. In addition, such PU-spanned ASE pairs tend to have a higher frequency of being included in transcript isoforms. ASE regions that overlap with PUs also have lower nonsynonymous-to-synonymous substitution rate ratios than those that do not overlap with PUs, indicating stronger negative selection pressure in PU-overlapped ASE regions. Of note, we show that PUs have protein domain- and structural orderness-independent effects on messenger RNA (mRNA) splicing. Overall, our results suggest that fine-scale protein structural requirements have significant influences on the splicing patterns of human mRNAs.
The evolution of the coding exome of the Arabidopsis species - the influences of DNA methylation, relative exon position, and exon length
(2014-06-25)
Chen, Feng-Chi
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Chuang, Trees-Juen
;
Lin, Hsuan-Yu
;
Hsu, Min-Kung
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生物科技學系
Background: The evolution of the coding exome is a major driving force of functional divergence both between species and between protein isoforms. Exons at different positions in the transcript or in different transcript isoforms may (1) mutate at different rates due to variations in DNA methylation level; and (2) serve distinct biological roles, and thus be differentially targeted by natural selection. Furthermore, intrinsic exonic features, such as exon length, may also affect the evolution of individual exons. Importantly, the evolutionary effects of these intrinsic/extrinsic features may differ significantly between animals and plants. Such inter-lineage differences, however, have not been systematically examined. Results: Here we examine how DNA methylation at CpG dinucleotides (CpG methylation), in the context of intrinsic exonic features (exon length and relative exon position in the transcript), influences the evolution of coding exons of Arabidopsis thaliana. We observed fairly different evolutionary patterns in A. thaliana as compared with those reported for animals. Firstly, the mutagenic effect of CpG methylation is the strongest for internal exons and the weakest for first exons despite the stringent selective constraints on the former group. Secondly, the mutagenic effect of CpG methylation increases significantly with length in first exons but not in the other two exon groups. Thirdly, CpG methylation level is correlated with evolutionary rates (d(S), d(N), and the d(N)/d(S) ratio) with markedly different patterns among the three exon groups. The correlations are generally positive, negative, and mixed for first, last, and internal exons, respectively. Fourthly, exon length is a CpG methylation-independent indicator of evolutionary rates, particularly for d(N) and the d(N)/d(S) ratio in last and internal exons. Finally, the evolutionary patterns of coding exons with regard to CpG methylation differ significantly between Arabidopsis species and mammals. Conclusions: Our results suggest that intrinsic features, including relative exonic position in the transcript and exon length, play an important role in the evolution of A. thaliana coding exons. Furthermore, CpG methylation is correlated with exonic evolutionary rates differentially between A. thaliana and animals, and may have served different biological roles in the two lineages.